Biology subjects

Zhang, C.-Y.

Publications and source records attributed to Zhang, C.-Y..

10 recordsLinked to original sources

bioRxiv2026

A multiscale cytoskeletal network model for shear rheological property and its evolutionary mechanism

The cytoskeleton is a dynamic biopolymer network whose shear rheological properties are crucial for cellular physiology and pathology. However, its mechanical behavior spans multiple spatiotemporal scales, and the coupling of dynamic remodeling and viscoelastic dissipation mechanisms poses a challenge for traditional models to comprehensively capture complex cellular responses. This study aims to establish a multiscale cytoskeletal network model that integrates the bio-chemo-mechanical properties of local linked proteins, the viscoelasticity of actin filaments, and their deformation states. Developing a boundary-modified finite element method with an incremental iterative algorithm, we demonstrated the dynamic remodeling of network and the resultant rheological properties of cytoskeleton by extending the predictive time scale to one thousand seconds. The results not only reproduced the short- and intermediate-term power-law creep behavior and long-term strain plateau response of the cytoskeletal network observed in shear rheological experiments, but also indicate that the synergy among the chemo-mechanical coupling of cross-linked proteins and the bending-to-tension transition of actin filaments govern both the network remodeling and its power-law response evolutionary, whereas the steady-state properties of actin filaments determine the long-term network behavior. Simulations of cancerous and drug effects show that cancer-induced softening and reduced filament viscosity lead to accelerated cytoskeletal responses and decreased apparent shear modulus, respectively; and drug-enhanced filament prestress, along with promoting association or inhibiting dissociation of cross-linked proteins, can effectively increase the steady-state shear modulus. These findings advance the understanding of the spatiotemporal evolution and pathological mechanisms of cellular mechanical responses and provide insights for regulating polymer network performance.

biophysics↗

bioRxiv2026

Experimental Time Points Guided Transcriptomic Velocity Inference

Time-series single-cell RNA sequencing enables longitudinal tracking of biological processes, yet cellular trajectory reconstruction informed by experimental time remains challenging. Existing trajectory inference methods either perform de novo reconstruction without leveraging experimental time points, or prioritize transitions between time points while paying less attention to intra-time-point dynamics. To reconcile experimental time points with local precision, we present CellDyc, a semi-supervised learning framework that leverages experimental time-point supervision to reconstruct transcriptomic velocities and recover an intrinsic gene-embedded time. CellDyc consistently outperforms existing approaches in reconstructing cellular trajectories across development, disease, and reprogramming contexts. Biologically, CellDyc provides novel insights, such as resolving temporal heterogeneity in erythroid maturation and quantitatively demonstrating that the immunosuppressive environment delays monocyte differentiation in glioblastoma. CellDyc integrates seamlessly with downstream tools like CellRank and remains robust even when only inferred temporal information is available. Collectively, CellDyc offers a rigorous, data-driven solution for deciphering time-resolved cellular dynamics.

bioinformatics↗

bioRxiv2024

Telomere-to-telomere genome assembly of a male goat reveals novel variants associated with cashmere traits

A complete goat (Capra hircus) reference genome enhances analyses of genetic variation, thus providing novel insights into domestication and selection in goats and related species. Here, we assembled a telomere-to-telomere (T2T) gap-free genome (2.86 Gb) from a cashmere goat (T2T-goat1.0), which included a Y chromosome of 20.9 Mb. With a base accuracy of >99.999%, T2T-goat1.0 corrected numerous genome-wide structural and base errors in previous assemblies and added 288.5 Mb of previously unresolved regions (PURs) and 446 newly assembled genes to the reference genome. We sequenced the genomes of five representative goat breeds for PacBio reads, and used T2T-goat1.0 as a reference to identify a total of 63,417 structural variations (SVs) with up to 4711 SVs (7.41%) in the PURs and 507 overlapping genes significantly enriched (Padj. < 0.05) in the keratin filament pathway. T2T-goat1.0 was applied in population analyses of global wild and domestic goats, which revealed 32,419 SVs and 25,397,794 SNPs, including 870 SVs and 545,026 SNPs in the PURs. Also, our analyses revealed a set of novel selective variants and genes associated with domestication (e.g., NKG2D and ABCC4) and cashmere traits (e.g., ABCC4 and ASIP).

genomics↗

bioRxiv2023

Spatial chromosome organization and adaptation of the radiation-resistant extremophile Deinococcus radiodurans

Radiation-resistant Deinococcus radiodurans is an extremophilic microorganism capable of withstanding high levels of ionizing radiation and chemical mutagens. It possesses remarkable DNA repair capability and serves as a model organism for studying stress resistance mechanism. However, our understanding on the spatial chromosome organization of this species remains limited. In this study, we employed chromosome conformation capture (3C) technology to determine the 3D genome structure of D. radiodurans and to further investigate the changes of chromosome conformation induced by ultraviolet (UV) irradiation. We observed that UV irradiation reduced short-range chromosome interactions, and smaller chromosomal interaction domains (CIDs) merged to form larger CIDs. Integrating transcriptomic data analysis, we found that the majority of upregulated differentially expressed genes were significantly enriched near specific CID boundaries. Specially, we comprehensively elucidated that the nucleoid-associated protein Dr_ebfC may serve as a global regulator for gene expression by altering chromosome structure, thereby influencing the physiological state of the bacterium. Overall, our study revealed the chromosome conformations of D. radiodurans under different conditions, and offered valuable insights into the molecular responses of this extremophile to environmental stresses.

systems biology↗

bioRxiv2023

Cryo-EM structures of human SID-1 transmembrane family proteins and implications for their low-pH-dependent RNA transport activity

Human SIDT1 and SIDT2 are closely related members of the systemic RNA interference (RNAi)-defective (SID-1) transmembrane family. Both mediate RNA internalization and intracellular transport and are involved in various biological processes. However, the molecular basis of RNA uptake, especially for exogenous small RNAs, remains elusive. Here, we present the cryo-electron microscopy (cryo-EM) structures of human SIDT1 and SIDT2. Both structures reveal the overall architecture of a dimeric arrangement contributed by the {beta}-strand-rich extracellular domain (ECD) and the transmembrane domain (TMD) with 11 passes, highlighting the remarkable structural congruence. The in situ assays confirm that SIDT1 and SIDT2 exist as dimers or higher-order oligomers. We demonstrate that for both SIDT1 and SIDT2, the ECD binds small RNAs, such as dietary plant-derived miRNA, only under acidic conditions. In addition, RNA binding under low pH can trigger higher-order assembly of the ECD dimer, suggesting the potential importance of oligomerization during RNA uptake. Our results illustrate the molecular features of the conserved SID-1 family proteins to elucidate the mechanism of the low pH-dependent activation of RNA uptake mediated by SIDT1 and SIDT2. This study provides a promising understanding of the molecular basis of the nucleic acid delivery platform, which may potentially open new avenues for the design and optimization of RNA-based therapies.

biochemistry↗

bioRxiv2023

Characterization of N-glycosylation and its Functional Role in SIDT1-Mediated RNA Uptake

The mammalian SID-1 transmembrane family members, SIDT1 and SIDT2, are multi-pass transmembrane proteins that mediate the cellular uptake and intracellular trafficking of nucleic acids, playing important roles in the immune response and tumorigenesis. Previous work has suggested that human SIDT1 and SIDT2 are N-glycosylated, but the precise site-specific N-glycosylation information and its functional contribution remain unclear. In this study, we employ high-resolution liquid chromatography tandem mass spectrometry to comprehensively map the N-glycosites and quantify the N-glycosylation profiles of SIDT1 and SIDT2. Further molecular mechanistic probing elucidates the essential role of N-linked glycans in regulating cell surface expression, RNA binding, protein stability, and RNA uptake of SIDT1. Our results provide crucial information about the potential functional impact of N-glycosylation in the regulation of SIDT1-mediated RNA uptake and provide insights into the molecular mechanisms of this promising nucleic acid delivery system, with potential implications for therapeutic applications.

biochemistry↗

bioRxiv2022

A novel pathway of functional microRNA uptake and mitochondria delivery

Extracellular miRNAs serve as signal molecules in the recipient cells. Uptake of extracellular miRNAs by the recipient cells and their intracellular transport, however, remains elusive. Here we show RNA phase separation as a novel pathway of miRNA uptake. In the presence of serum, synthetic miRNAs rapidly self-assembly into [~]110nm discrete nanoparticles which enable miRNAs entry into different cells. Depleting serum cationic proteins prevents the formation of such nanoparticles and thus blocks miRNA uptake. Different from lipofectamine-mediated miRNA transfection in which the majority of miRNAs are in lysosomes of transfected cells, nanoparticles-mediated miRNA uptake predominantly delivers miRNAs into mitochondria in a polyribonucleotide nucleotidyltransferase 1-dependent manner. Functional assays further show that the internalized miR-21 via miRNA phase separation enhances mitochondrial translation of Cytochrome b, leading to increase in ATP and ROS reduction in HEK293T cells. Our findings reveal a previously unrecognized mechanism for uptaking and delivering functional extracellular miRNAs into mitochondria. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/515397v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1b83cd8org.highwire.dtl.DTLVardef@a29f54org.highwire.dtl.DTLVardef@8a6b1aorg.highwire.dtl.DTLVardef@17d9d2a_HPS_FORMAT_FIGEXP M_FIG C_FIG RNA phase separation-based extracellular miRNA uptake and PNPT1-mediated mitochondrial delivery of internalized miRNAs O_LImiRNAs can self-assembly into [~]110nm nanoparticles to enter various cells in the presence of serum C_LIO_LImiRNA phase separation is mediated by serum cationic proteins C_LIO_LIInternalized miRNAs via this nanoparticle pathway are predominantly delivered to mitochondria C_LIO_LIMitochondrial delivery of the internalized miRNAs is mediated by PNPT1 C_LI

cell biology↗

bioRxiv2022

Comprehensive integration of single-cell transcriptomic data illuminates the regulatory network architecture of plant cell fate specification

Plant morphogenesis relies on precise gene expression programs at the proper time and position which is orchestrated by transcription factors (TFs) in intricate regulatory networks at a cell-type specific manner. Here we presented a reference single-cell transcriptomic atlas of Arabidopsis seedlings by integration of 40 published scRNA-seq datasets from representative tissues as well as the entire under- and above-ground parts. We identified 34 distinct cell types or states, largely expanding our current view of plant cell compositions. We then mapped the developmental trajectory of root-shoot lineage separation and identified differential gene expression programs that may regulate the cell fate determination of under- and above-ground organs. Lastly, we systematically constructed cell-type specific gene regulatory networks and uncovered key regulators that act in a coordination manner to control cell-type specific gene expression. Taken together, our study not only offers a valuable resource plant cell atlas exploration but also provides molecular insights into gene-regulatory programs that determines organ specify, particularly the differentiation between root and shoot.

bioinformatics↗

bioRxiv2020

Size Effect on Structure and Stiffness of Viral DNA during Temperature Variation

Structure and stiffness of nucleic acids are closely related to viral infectivity. The article is aimed to clarify a recent controversy on structure variation of viral DNA in temperature-dependent experiments. A multi-scale correlation between microscopic structure of viral DNA and its bulk stiffness is formulated by presenting a two-zone mesoscopic free energy model. Results reveal that the increasing temperature promotes DNA structure transformation from order to disorder, and leads to size effect on temperature-dependency of stiffness and structure of viral DNA.

biophysics↗

bioRxiv2020

Accurate Diagnosis of Colorectal Cancer Based on Histopathology Images Using Artificial Intelligence

BackgroundAccurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on their daily image analyses. MethodsBased on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC prediction/diagnosis using weakly labeled pathological whole slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, >14,680 WSIs, from >9,631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, U.S., and Germany. ResultsOur innovative AI tool was consistently nearly perfectly agreed with (average Kappa-statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multi-centers. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.981 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. ConclusionsThis first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. Hence, it will drastically alleviate the heavy clinical burden of daily pathology diagnosis, and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.

pathology↗